Initially, 6 mg subcutaneously. If migraine symptoms return, a second 6 mg dose may be given with a minimum 1-hour interval between doses. The maximum dose within 24 to 48 hours is two 6 mg injections. If side effects are limiting, a lower dose may be used. Controlled clinical trials have failed to show that clear benefit is associated with the administration of a second 6 mg dose in patients who have failed to respond to a first injection. A cardiovascular evaluation is recommended in triptan-naive patients who have multiple cardiovascular risk factors (e.g., older age, diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease). A dose-ranging efficacy study showed that, although pain relief occurred faster with 6 mg and 8 mg doses, doses as low as 1 mg were significantly more efficacious than placebo. The incidence of adverse effects was highest (93%) with the 8 mg dose compared to the 6, 4, or 3 mg doses (about 80%). Headache relief within 1 hour (defined as a reduction in pain from severe or moderately severe to mild or no headache) was achieved in 73% of patients who received a single 6 mg subcutaneous dose of sumatriptan compared to 50% of patients who received a single 4 mg subcutaneous dose.

Adolescents† and Children 6 to 17 years†

Safety and efficacy have not been established. One open investigation in 17 children used single doses of 3 to 6 mg SC. Rare but serious adverse events have been reported in adolescents with parenteral use of sumatriptan. Further study is needed before these doses can be recommended.

Subcutaneous dosage (Zembrace SymTouch)

Adults

3 mg injected subcutaneously. The maximum cumulative daily dose is 12 mg. One injection may be given up to 4 times a day with each injection at least 1 hour apart. A cardiovascular evaluation is recommended in triptan-naive patients who have multiple cardiovascular risk factors (e.g., older age, diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease).

Oral dosage

Adults

In patients without significant vomiting, administer a single dose of 25 to 100 mg PO as early as possible after the onset of symptoms. The maximum recommended single dose is 100 mg PO. A 50 mg or 100 mg dose may provide a greater effect than a 25 mg dose; however, a 100 mg dose may not provide a greater effect than a 50 mg dose. If a satisfactory response has not been obtained at 2 hours, a second dose of up to 100 mg may be given. If headache returns, additional oral doses may be taken at intervals of at least 2 hours up to a maximum dose of 200 mg/day. If headache returns following initial treatment with sumatriptan injection, additional oral doses of up to 100 mg/day total may be given with intervals of at least 2 hours between each oral dose. A cardiovascular evaluation is recommended in triptan-naive patients who have multiple cardiovascular risk factors (e.g., older age, diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease).

Transdermal dosage

Adults

Apply 1 iontophoretic transdermal system (TDS) to dry intact, non-irritated skin on the upper arm or thigh. Each TDS delivers 6.5 mg of sumatriptan over 4 hours. Once applied, the activation button must be pushed, and the red light emitting diode (LED) will turn on. The TDS must be applied and activated within 15 minutes of initiation of assembly. The TDS should remain in place for 4 hours or until the red LED light goes off. If the light turns off before 4 hours, dosing has stopped and the TDS can be removed. Once dosing is completed, the system cannot be reactivated. If headache relief is incomplete, a second TDS can be applied to a different site. The maximum recommended single dose is one TDS. No more than two TDS should be used in any 24 hour period, and the second TDS should be applied no sooner than 2 hours after activation of the first TDS. There is no evidence of benefit for the use of a second TDS to treat headache recurrence or incomplete headache relief during a migraine attack. The safety of using more than 4 TDS in one month has not been established. A cardiovascular evaluation is recommended for triptan-naive patients who have multiple cardiovascular risk factors (e.g., older age, diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease.)

Intranasal dosage (Imitrex nasal spray and generic equivalents)

Adults

5 or 10 mg (1 or 2 sprays, respectively) into 1 nostril as a single dose or 20 mg (1 spray) into 1 nostril as a single dose. If headache returns, the dose may be repeated once after 2 hours, not to exceed 40 mg/day. In controlled clinical trials, single doses of 5, 10, or 20 mg administered into one nostril were effective. A greater proportion of patients had headache response following a 20 mg dose than following a 5 mg or 10 mg dose. Therefore, the dose should be individualized. Single doses above 20 mg do not provide greater effect than 20 mg doses. A cardiovascular evaluation is recommended in triptan-naive patients who have multiple cardiovascular risk factors (e.g., older age, diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease).

Intranasal dosage (Onzetra Xsail powder)

Adults

22 mg of nasal powder (2 nosepieces with 11 mg in each nostril) administered nasally using the Xsail breath-powered delivery device. Dose may be repeated after at least 2 hours after the first dose if the migraine has not resolved by 2 hours or the migraine returns after transient improvement. Do not exceed a total daily dose of 44 mg (4 nosepieces) or 1 dose of nasal powder and 1 dose of another sumatriptan product. The safety of treating 4 or more headaches in a 30 day period has not been established. A cardiovascular evaluation is recommended in triptan-naive patients who have multiple cardiovascular risk factors (e.g., older age, diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease).

Initially, 6 mg subcutaneously. If headache symptoms return, a second 6 mg dose may be given with a minimum 1-hour interval between doses. Consider giving a second dose only if some response to the first dose was observed. The maximum dose within 24 to 48 hours is two 6 mg injections. A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease).

DOSING CONSIDERATIONS

Hepatic Impairment

Hepatic impairment may cause unpredictable increases in the bioavailability of orally administered sumatriptan. Do not exceed 50 mg/dose PO. Hepatic impairment does not significantly affect intranasal or subcutaneous sumatriptan. All formulations are contraindicated for use in patients with severe hepatic impairment.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Intermittent hemodialysisIt is not known whether hemodialysis removes sumatriptan from plasma.

Peritoneal dialysisIt is not known whether peritoneal dialysis removes sumatriptan from plasma.

ADMINISTRATION

Oral Administration

Oral Solid Formulations

To avoid unpleasant taste swallow tablets whole; do not crush or chew.Take with fluids.

Imitrex injectable solution and generic equivalents:In patients with identifiable cardiovascular risk factors, the initial dose should be given in the physician's office in order to observe if there is any unrecognized cardiovascular disease.In patients receiving doses other than 4 or 6 mg, only the 6 mg single dose vial should be used.Inject subcutaneously preferably into the lateral portion of the thigh or deltoid area.For patients who are self administering sumatriptan, adequate oral as well as written instructions on the use of the auto-injector should be supplied before they self-administer a dose.

Sumavel DosePro needle-free system:Sumavel is provided as a single use system; discard after use.Visually inspect device prior to administration. Snap-off tip should sit firmly on end of clear medication chamber; if the snap-off tip is tilted or broken, do not use product.Visually inspect product within clear medication chamber for particulate matter and discoloration. Product should be clear to pale yellow; if product appears dark-colored or cloudy, do not use product.Clean and dry delivery site prior to administration.Remove the snap-off tip using a firm downward motion; do not twist or pull. Prepare the dose by pressing the green lever down until it clicks and locks into the handle. From this point on, do not touch the end of the medication chamber; keep chamber pointed away from face and eyes.Pinch 2 inches of skin on the thigh or abdomen; do not administer into scars or moles, or within 2 inches of the navel. Place medication chamber against skin and press device straight down to deliver the subcutaneous dose.Rotate delivery site with each use. Avoid administration into other areas of the body, including the arm.

Zymbrace SymTouch autoinjector:The autoinjector is a prefilled, ready-to-use, single dose device; discard after use.Inspect the appearance of the medicine through the medicine window. The solution should be a clear, colorless to pale yellow. Do not use if the solution is discolored or contains lumps, flakes, or particles.The needle penetrates approximately one-fourth inch (6 mm). Use injection sites with adequate skin and subcutaneous thickness. Recommended injection sites are the lateral portion of the thigh or deltoid area.Hold the autoinjector in one hand, and pull the red cap straight off.Place the autoinjector at a 90 degree angle at the skin injection site with the yellow needle guard gently pressed against the skin.Press and hold the autoinjector down against the skin. Continue to hold the device down until 2 audible clicks occur. After the second click, wait 5 seconds before removing the autoinjector to ensure the full dose is delivered.Confirm that the red plunger rod has filled the medicine viewing window. This indicates a full dose has been delivered.

Topical Administration

Transdermal Patch Formulations

The sumatriptan transdermal system (TDS) should not be cut.The TDS should be applied to an area of skin on the upper arm or thigh that is dry, clean and relatively hair free. Instruct patients not to apply the TDS over scars, tattoos, scratches, burns, abrasions, broken skin, or over skin that is red or irritated. Skin should be free of redness and irritation for at least 3 days prior to application.If a second TDS is required because headache relief is incomplete, a second TDS can be applied at least 2 hours after the first is activated. apply to a different site. Do not apply a new TDS to a previous application site until the site remains erythema free for at least 3 days.Instruct patients to carefully follow the instructions for use dispensed with each prescription to ensure appropriate application and activation of the TDS. The TDS must be activated within 15 minutes of initiating step 1 (pull tabs) or the TDS will not operate.The TDS may be taped down with medical tape if it begins to peel off. Instruct patients not to bathe, shower, or swim while wearing the TDS; the TDS must be kept dry.Patients should not have a Magnetic Resonance Imaging (MRI) while wearing the TDS.Patients may feel slight tingling or a mild burning sensation within 30 seconds of activating the TDS; however, the TDS should be removed if the patient experiences a painful burning sensation during use.The TDS should be removed slowly to minimize skin irritation and the area cleansed with mild soap and water to remove any medicine that might be left on the skin. Most patients experience some skin redness under the transdermal system, which usually disappears in 24 hours.To dispose of the TDS, it should be folded so the adhesive side sticks to itself and safely thrown away.

Inhalation Administration

Intranasal Inhalation Administration

Imitrex nasal spray solution and generic equivalents:Instruct patient on proper administration technique.After administration, rinse the tip of the bottle with hot water, taking care not to suck water into the bottle, and dry with a clean tissue. Replace the cap right after cleaning.To avoid the spread of infection, do not use the container for more than one person.

Onzetra Xsail nasal powder:Each nosepiece contains one dose of 11 mg of sumatriptan.Remove the clear device cap from the reusable delivery device.Remove a nosepiece from the foil pouch, and click the nosepiece into the device body.Fully press and then release the white piercing button on the device to pierce the capsule in the nosepiece. Only press the button once.Insert the nosepiece into the nostril and create a tight seal.Rotate the device to place the mouthpiece into the mouth. Blow forcefully into the mouthpiece to deliver the nasal powder into the nostril. Vibration may occur, which indicates that the patient is blowing forcefully as directed.Once the medication has been delivered, discard the nosepiece.Repeat the process to administer the drug into the other nostril.

STORAGE

Alsuma:- Discard product if it contains particulate matter, is cloudy, or discolored- Discard unused portion. Do not store for later use.- Protect from light- Store between 36 to 77 degrees F- Store in original containerImitrex:- Discard product if it contains particulate matter, is cloudy, or discolored- Discard unused portion. Do not store for later use.- Protect from light- Store between 36 to 77 degrees F- Store in original containerImitrex Statdose:- Discard product if it contains particulate matter, is cloudy, or discolored- Discard unused portion. Do not store for later use.- Protect from light- Store between 36 to 77 degrees F- Store in original containerMigraine Pack:- Store at controlled room temperature (between 68 and 77 degrees F)ONZETRA:- Do not freeze- Do not refrigerate- Product should always be stored in the blister and only removed immediately before use- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees FSumavel DosePro System:- Discard product if it contains particulate matter, is cloudy, or discolored- Discard unused portion. Do not store for later use.- Protect from light- Store between 36 to 77 degrees F- Store in original containerZecuity:- Do not freeze- Do not refrigerate- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees FZEMBRACE:- Protect from light- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

General Information

The sumatriptan iontophoretic transdermal system (TDS) should not be applied in areas near or over electrically-active implantable or body-worn medical devices (e.g., implantable cardiac pacemaker, body-worn insulin pump, implantable deep brain stimulator).

Sumatriptan hypersensitivity

Sumatriptan is contraindicated in patients with sumatriptan hypersensitivity or any components of the commercially available products; use sumatriptan cautiously in patients who have experienced allergic contact dermatitis (ACD) with the iontophoretic transdermal system (TDS). Patients sensitized from use of the sumatriptan TDS, as evidenced by development of ACD, may develop systemic sensitization or other systemic reactions if sumatriptan-containing products are taken via other routes, e.g., orally or subcutaneously. It is possible that some patients who developed ACD with sumatriptan by exposure to the sumatriptan TDS, and who have developed systemic sensitization, may not be able to take sumatriptan in any form. Patients who develop ACD with the sumatriptan TDS and require treatment with sumatriptan via other routes should receive their first subsequent dose under close medical supervision.

Rare, but serious adverse cardiac effects, including heart attacks, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours of receiving 5-HT1 agonists. Many of these patients had concurrent cardiovascular risk factors; therefore, it is difficult to assess causality. Sumatriptan and other 5-HT agonists may cause coronary vasospasm, and therefore are contraindicated in patients with known or suspected coronary artery disease (CAD), angina pectoris, vasospastic angina such as Prinzmetal's variant angina, arteriosclerosis, silent myocardial ischemia, acute myocardial infarction, history of myocardial infarction, or other significant cardiac disease. Patients with CAD risk factors (e.g., high blood pressure, diabetes mellitus, hypercholesterolemia, obesity, tobacco smoking, family history of CAD, female with surgical or physiological menopause, or male > 40 years old) should not be given sumatriptan unless a cardiac evaluation determines they are reasonably free of CAD, myocardial ischemia or other significant cardiac disease. Patients who are long-term users of sumatriptan and who have or acquire risk factors predictive of CAD should undergo periodic cardiac evaluation. For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiac evaluation, the first dose of sumatriptan should be given in a controlled setting such as a clinic or physician's office. ECG monitoring is strongly encouraged due to the possibility of asymptomatic cardiac ischemia during the time immediately following sumatriptan administration in patients with risk factors. Inappropriate concomitant use of eletriptan and sumatriptan may have contributed to a fatal myocardial infarction in a patient with known cardiovascular risk factors; however, causality was not definitively determined. In addition, patients with cardiac arrhythmias should not receive sumatriptan as rhythm disturbances have been reported with the use of 5-HT1 agonists. Sumatriptan is contraindicated in patients with Wolff-Parkinson-White syndrome or cardiac arrhythmias associated with other cardiac accessory conduction pathway disorders.

Hypertension

Sumatriptan is contraindicated in patients with uncontrolled hypertension. Sumatriptan can produce a significant increase in blood pressure in patients with and without a history of hypertension. Patients with controlled hypertension may experience mild and transient elevations in blood pressure.

Cerebrovascular disease, intracranial bleeding, stroke

Sumatriptan is contraindicated in patients with cerebrovascular disease (i.e., stroke or transient ischemic attacks) and should be avoided in the presence of intracranial bleeding due to the vasospastic effects of 5-HT agonists. While stroke, cerebral hemorrhage, and related fatalities have been reported following administration of 5-HT1 agonists, these events may have been present prior to administration of the drug, and the drug was mistakenly given in response to the cerebrovascular symptoms. However, patients with migraines may be at an increased risk for cerebrovascular events (e.g., stroke, hemorrhage).

Basilar/hemiplegic migraine

Sumatriptan is contraindicated in basilar/hemiplegic migraine because safety and efficacy have not been established. Safety and efficacy have not been established in cluster headaches. Sumatriptan should not be administered if the headache is atypical for the patient. Sumatriptan is not recommended for long-term prophylaxis of migraine headaches.

Intravenous administration

Intravenous administration of sumatriptan should be avoided because of the potential to cause coronary vasospasm.

Pregnancy

A consistent pattern of birth defects among pregnant women exposed to sumatriptan has not been observed. The sumatriptan prospective pregnancy registry collected pregnancy outcomes of 528 infants and fetuses with earliest sumatriptan exposure during the first trimester, 78 during the second trimester, and 16 during the third trimester. The incidence of major birth defects during first trimester exposure was 4.2% (20/478 [95% CI 2.6% to 6.5%]) and during any trimester exposure was 4.2% (24/576 [95% CI 2.7% to 6.2%]). Birth defects reported for more than 2 infants after first trimester exposure included ventricular septal defects (n = 4) and pyloric stenosis (n = 3). Fetal deaths, spontaneous abortions, and elective abortions without reported defects were excluded from analysis. An analysis of data from the Swedish Medical Birth Register reported a relative risk of malformations of 0.99 (107/2,257 [95% CI 0.91 to 1.21]) among live births with first trimester exposure to sumatriptan. A study of the Norwegian birth registry and prescription data reported congenital malformations in 15 infants of 415 women who redeemed prescriptions for sumatriptan during the first trimester of pregnancy, and in 20 infants of 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy. Compared to a general population group, the odds ratio for congenital malformation was 1.16 (95% CI 0.69 to 1.94) among women who redeemed prescriptions for sumatriptan during the first trimester and 1.83 (95% CI 1.17 to 2.88) for those who redeemed prescriptions for sumatriptan before pregnancy. During animal reproductive studies, intravenous administration of sumatriptan to rabbits during organogenesis resulted in an increased incidence of embryolethality with a no-effect dose of 0.75 mg/kg/day, which is approximately one tenth of the maximum single oral dose of 100 mg based on body surface area. In rats and rabbits, oral treatment with sumatriptan was associated with fetal abnormalities and pup mortality at doses higher than the maximum single recommended human oral dose based on body surface area.

Breast-feeding

Sumatriptan is excreted into the breast milk of humans. Previous American Academy of Pediatrics recommendations considered sumatriptan to be compatible with breast-feeding. Infant exposure to sumatriptan can be minimized by avoiding breast-feeding for 12 hours after treatment. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for sumatriptan and any potential adverse effects on the breast-fed infant from sumatriptan or the underlying maternal condition. In 1 trial, 5 women who had been lactating for an average of 22 weeks received a single 6 mg subcutaneous dose of sumatriptan. Drug concentrations were measured in milk and plasma over an 8 hour period after drug administration. The mean milk:plasma ratio of sumatriptan was 4.9 (95% CI 4.1 to 5.7), indicating a significant transfer of sumatriptan into the milk compartment. However, only 0.24% (14 mcg; CI 6.1 to 22.7 mcg) of the 6 mg sumatriptan dose was recovered in the milk, which corresponds to a weight-adjusted mean exposure of 3.5% (95% CI 0.3% to 6.7%) of the maternal dose. Assuming oral bioavailability of sumatriptan in infants is similar to adults (mean 14%), the weight-adjusted infant dose is roughly 0.49%. Allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in the very premature neonate to 0.7% in a 30 week old infant (mean 3.5%). The authors of this study concluded that expressing breast milk and discarding it up to 8 hours after a dose would help to avoid any potential infant exposure to sumatriptan.

Hepatic disease

All formulations of sumatriptan are contraindicated in patients with severe hepatic disease or impairment. Sumatriptan is metabolized significantly by the liver. The bioavailability and peak serum concentrations can increase markedly in patients with hepatic disease. The oral formulation should be used cautiously in those with mild to moderate hepatic impairment; dosage adjustments are recommended if treatment with the oral formulation is deemed necessary.

Renal disease, renal failure, renal impairment

Sumatriptan is renally excreted; therefore, renal impairment may contribute to an increase in bioavailability. Sumatriptan should be used with caution in patients with renal impairment, including renal disease or renal failure.

Children

Sumatriptan is not approved in children under 18 years for the treatment of migraine and the manufacturer does not recommend its use. However, there are studies of sumatriptan for the treatment of migraine in children. Serious post-marketing adverse events have been reported in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan.

Geriatric

A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD). Generally, dose selection should be cautious, starting at the lower end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiovascular function and of concomitant disease or drug therapy.

Driving or operating machinery

Patients should be warned about the possibility of sedation while taking sumatriptan and to use caution when driving or operating machinery.

Colitis, peripheral vascular disease, Raynaud's phenomenon

Sumatriptan is contraindicated in patients with peripheral vascular disease including ischemic bowel disease (ischemic colitis) and Raynaud's phenomenon. Sumatriptan may cause vasospastic reactions leading to vascular and colonic ischemia with abdominal pain and bloody diarrhea.

Seizure disorder, seizures

There have been rare reports of seizure following administration of sumatriptan. Sumatriptan should be used with caution in patients with a history of seizures (seizure disorder) or structural brain lesions that lower their seizure threshold.

Visual disturbance

Rare reports of transient and permanent blindness, including significant partial vision loss have been reported with the use of sumatriptan. Visual disturbance may be a part of any type of migraine headache; therefore, causality cannot be determined.

MAOI therapy

Sumatriptan is contraindicated in patients currently receiving MAOI therapy (i.e., MAO-A inhibitors) or those who have received an MAO-A inhibitor within the previous 2 weeks. Sumatriptan is also contraindicated in patients who have received other 5-HT1 agonists, ergotamine-containing medications, or ergot-type medications within 24 hours of sumatriptan administration.

Magnetic resonance imaging (MRI)

The sumatriptan iontophoretic transdermal system (TDS) contains metal parts. The TDS must be removed before a magnetic resonance imaging (MRI) procedure to prevent injury during the procedure.

DRUG INTERACTIONS

Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Acetaminophen; Dextromethorphan: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Acetaminophen; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor agonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Acetaminophen; Tramadol: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist. Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Amitriptyline; Chlordiazepoxide: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Amoxapine: (Moderate) Amoxapine should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Amoxapine, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs), including reducing the uptake of norepinephrine and serotonin. Amoxapine rarely causes serotonin syndrome when used alone, but the risk may be increased when combined with other serotonergic agents. Amphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Amphetamine; Dextroamphetamine Salts: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Amphetamine; Dextroamphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Aspirin, ASA; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor agonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. Benzphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Bromocriptine: (Major) Bromocriptine is an ergot alkaloid derivative. Serotonin-receptor agonists (e.g., "triptans" such as almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) are contraindicated for use within 24 hours of treatment with traditional ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of serotonin-receptor agonists. While interactions have not been specifically reported between bromocriptine and triptans, combined use of these agents should be avoided if possible. Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Buprenorphine: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as selective serotonin-receptor agonists ('triptans'), has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment with buprenorphine and a triptan is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Buprenorphine; Naloxone: (Major) Concurrent use of opioids with other drugs that modulate serotonergic function, such as selective serotonin-receptor agonists ('triptans'), has resulted in serotonin syndrome in some cases. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. If combination treatment with buprenorphine and a triptan is required, patients should be carefully observed, particularly during treatment initiation and during dose adjustments of the serotonergic drug; discontinue buprenorphine if serotonin syndrome is suspected. Buspirone: (Moderate) Buspirone should be used cautiously with serotonin-receptor agonists. Pharmacologically, buspirone is a serotonin agonist, and using in conjunction with other serotonin agonists could result in serotonin syndrome, which can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonin-agonists and buspirone should be informed of the signs and symptoms of serotonin syndrome. Butorphanol: (Moderate) The safety of using intranasal butorphanol and sumatriptan nasal spray during the same episode of migraine has not been established; however, it should be noted that both products are capable of producing transient increases in blood pressure. Theoretically, the effect of intranasal butorphanol may be increased by intranasal sumatriptan. To reduce the likelihood of this interaction, allow 30 minutes between the administration of each drug. In healthy volunteers, the pharmacokinetics of butorphanol intranasal (1 mg) were not affected by the coadministration of a single dose of sumatriptan SC 6 mg. However, in another study, the pharmacokinetics of butorphanol were significantly altered (29% decrease in AUC and 38% decrease in Cmax) when butorphanol intranasal (1 mg) was administered 1 minute after a 20-mg dose of sumatriptan nasal spray (in opposite nostrils); however, if patients wait 30 minutes between administrations any interaction effect should be minimal. Butorphanol intranasal administration does not affect the pharmacokinetics of sumatriptan when given intranasally. Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Chlorpheniramine; Dextromethorphan: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Citalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Clomipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Desipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Desvenlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like desvenlafaxine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome is characterized by mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, death. If serotonin syndrome occurs, all serotonergic drugs should be discontinued and appropriate medical treatment should be initiated. Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Dextroamphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Dextromethorphan: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Dextromethorphan; Guaifenesin: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Dextromethorphan; Promethazine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Dextromethorphan; Quinidine: (Moderate) Dextromethorphan inhibits serotonin reuptake and therefore should be used cautiously with serotonin-receptor agonists as serotonin syndrome may result. Serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. Patients receiving serotonergic drugs in combination should be informed of the signs and symptoms of serotonin syndrome. Doxepin: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Droxidopa: (Major) Coadministration of droxidopa with other agents that increase blood pressure, such as serotonin-receptor agonists, would be expected to increase the risk for supine hypertension. Monitor supine blood pressure. Reduce or discontinue droxidopa if supine hypertension persists. If supine hypertension is not well-managed, droxidopa may increase the risk of cardiovascular events. Duloxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like duloxetine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen. Ergot alkaloids: (Severe) Serotonin-receptor agonists (triptans) are contraindicated for use within 24 hours of treatment with ergot alkaloids (e.g., dihydroergotamine, methysergide) or ergot-type medications to avoid the potential for serious coronary ischemia. Ergot alkaloids have been reported to cause prolonged vasospastic reactions which may be additive with the effects of triptans. Additionally, ergot alkaloids are serotonergic agents whose effects on serotonin may be additive to those of the serotonin-receptor agonists. Escitalopram: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Fluoxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Fluoxetine; Olanzapine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Fluvoxamine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. Ibuprofen; Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor agonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Imipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Isocarboxazid: (Severe) Concurrent administration of MAO-A inhibitors or use of sumatriptan within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated. Sumatriptan appears to metabolized by monoamine oxidase (MAO), predominantly MAO-type A; therefore, plasma concentrations of sumatriptan may be increased by concurrent use of selective MAO-A inhibitors (e.g., meclobemide) or non-selective MAO-A and MAO-B inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid). Because oral sumatriptan usually undergoes first-pass metabolism, the increase of AUC after coadministration of an MAO-A inhibitor is greater than the interaction with subcutaneous sumatriptan combined with an MAO-A inhibitor. The effects of an MAOI on the AUC after intranasal sumatriptan use would be expected to be greater than the effect after sumatriptan SC but smaller than the effect after sumatriptan PO. In a study of healthy female volunteers (n=14), pretreatment with an MAO-A inhibitor (moclobemide) decreased the clearance of subcutaneous sumatriptan resulting in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life. The interaction was not evident with an MAO-B inhibitor (e.g., selegiline). In a similar study of oral sumatriptan, pretreatment with an MAO-A inhibitor followed by 25-mg PO of sumatriptan resulted in an approximately 7-fold increase in sumatriptan AUC. Levomilnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like levomilnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen. Linezolid: (Major) Linezolid is an antibiotic that is also a reversible, non-selective inhibitor of MAO and should not be administered with serotonin-receptor agonists. The monoamine oxidase type A enzyme metabolizes serotonin. Non-selective MAO inhibitors increase the plasma concentrations of these drugs and some of their active metabolites, thus increasing levels of serotonin. This interaction could lead to serotonin syndrome. The manufacturers of serotonin agonists contraindicate the administration of their drugs to patients receiving non-selective MAO inhibitors like linezolid or within 2 weeks of discontinuation of a MAO inhibitor. Lisdexamfetamine: (Major) Serotonin syndrome may occur during coadministration of drugs with serotonergic properties such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic drugs if serotonin syndrome occurs and implement appropriate medical management. Lithium: (Major) There is an increased risk of serotonin syndrome during concurrent use of drugs with central serotonergic properties such as lithium and serotonin-receptor agonists. Signs and symptoms of serotonin syndrome include autonomic instability (e.g., labile blood pressure, tachycardia, diaphoresis, dizziness, hyperthermia), mental status changes (e.g., delirium, confusion, coma), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), gastrointestinal effects (e.g., nausea, vomiting, diarrhea), seizures, and in rare cases, death. If concurrent use is necessary, monitor for the emergence of serotonin syndrome and inform patients of the increased risk. If serotonin syndrome is suspected, serotonergic agents should be discontinued and appropriate medical treatment should be implemented. Lorcaserin: (Major) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, serotonin-receptor agonists. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms. Maprotiline: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects. Meperidine: (Moderate) Serotonin-receptor agonists are associated with decreased serotonin reuptake and thus, increased serotonin concentrations. They should be used cautiously in conjunction with meperidine, as meperidine blocks the neuronal reuptake of serotonin. Taking these drugs together may increase the risk for serotonin syndrome. While uncommon, serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever Meperidine; Promethazine: (Moderate) Serotonin-receptor agonists are associated with decreased serotonin reuptake and thus, increased serotonin concentrations. They should be used cautiously in conjunction with meperidine, as meperidine blocks the neuronal reuptake of serotonin. Taking these drugs together may increase the risk for serotonin syndrome. While uncommon, serotonin syndrome can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever Methamphetamine: (Major) Serotonin syndrome may occur during coadministration of serotonergic drugs such as amphetamines and serotonin-receptor agonists. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Although unlikely to occur during monotherapy with serotonin-receptor agonists (or "triptans"), serotonin syndrome may occur from combining these drugs with other medications that potentiate serotonin activity. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management. Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. Methylene Blue: (Major) Theoretically, concurrent use of methylene blue and serotonin-receptor agonists may increase the risk of serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and serotonin-receptor agonists increase central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. Milnacipran: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like milnacipran with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen. Mirtazapine: (Major) Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when mirtazapine is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment. Morphine: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. Morphine; Naltrexone: (Major) Because of the potential risk and severity of serotonin syndrome, caution and careful monitoring are recommended when coadministering drugs that have serotonergic properties such as morphine and serotonin-receptor agonists. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Morphine and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. Nefazodone: (Major) Medications that augment release, decrease the metabolism of, or decrease the reuptake of serotonin, like the serotonin-receptor agonists, may interact with nefazodone by causing serotonin-related side effects, including serotonin syndrome. Whenever possible, these drug combinations should be avoided. If serotonin-syndrome is suspected, offending agents should be discontinued. Nortriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Oxycodone: (Major) Serotonin syndrome can occur during concomitant use of opiate agonists with serotonergic drugs, such as serotonin-receptor agonists. Symptoms may occur hours to days after concomitant use, particularly after dose increases. Serotonin syndrome may occur within recommended dose ranges. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage increases of either agent. Instruct patients to immediately report symptoms of agitation, hallucinations, tachycardia, fever, excessive sweating, shivering or shaking, muscle twitching or stiffness, trouble with coordination, nausea, vomiting, or diarrhea. Paroxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Perphenazine; Amitriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Phenelzine: (Severe) Concurrent administration of sumatriptan and an MAO-A inhibitor or use of sumatriptan within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated. Sumatriptan appears to be metabolized by monoamine oxidase (MAO), predominantly MAO-type A; therefore, plasma concentrations of sumatriptan may be increased by concurrent use of selective MAO-A inhibitors (e.g., meclobemide) or non-selective MAO-A and MAO-B inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid). Because oral sumatriptan usually undergoes first-pass metabolism, the increase of AUC after coadministration of an MAO-A inhibitor is greater than the interaction with subcutaneous sumatriptan combined with an MAO-A inhibitor. The effects of an MAOI on the AUC after intranasal sumatriptan use would be expected to be greater than the effect after sumatriptan SC but smaller than the effect after sumatriptan PO. In a study of healthy female volunteers (n=14), pretreatment with an MAO-A inhibitor (moclobemide) decreased the clearance of subcutaneous sumatriptan resulting in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life. The interaction was not evident with an MAO-B inhibitor (e.g., selegiline). In a similar study of oral sumatriptan, pretreatment with an MAO-A inhibitor followed by 25-mg PO of sumatriptan resulted in an approximately 7-fold increase in sumatriptan AUC. Protriptyline: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Rasagiline: (Minor) Cases of serotonin syndrome have been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs) that inhibit MAO-A. Since rasagiline selectively inhibits MAO-B at recommended doses, no interaction with sumatriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with rasagiline may increase central serotonin levels through MAO-A inhibition, increasing the risk for serotonin syndrome. However, whether or not 5-HT1B/1D agonists such as sumatriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. In addition, sumatriptan is partially metabolized by MAO-A, and a substantial increase in systemic exposure of sumatriptan has occurred during combined use with non-selective MAO-A inhibitors. No effects on sumatriptan pharmacokinetics have been observed with selective MAO-B inhibitors. Remifentanil: (Moderate) Concurrent use of remifentanil with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. If concurrent use is necessary, closely monitor the patient, particularly during remifentanil initiation and dosage adjustment. Discontinue remifentanil if serotonin syndrome is suspected. Selective serotonin reuptake inhibitors: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Selegiline: (Major) Serotonin syndrome has been reported during co-administration of serotonin-receptor agonists and monoamine oxidase inhibitors (MAOIs). Since oral selegiline selectively inhibits MAO-B at recommended doses, no interaction with sumatriptan would be expected with normal prescription use. However, there is a decline in MAO-B selectivity with increasing doses. Therefore, high dose treatment with oral selegiline may increase central serotonin levels through MAO-A inhibition. In addition, selegiline, transdermal inhibits both MAO-A and MAO-B at the usual antidepressant doses. However, whether or not 5-HT1B/1D agonists such as sumatriptan can cause serious cases of serotonin syndrome when used with serotonergic drugs has been debated since serotonin syndrome is thought to result primarily from 5-HT2A activation. Some serotonin-receptor agonists, such as sumatriptan are partially metabolized by MAO-A. Theoretically, use of high dose selegiline could increase systemic exposure to sumatriptan through MAO-A inhibition. Sertraline: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering selective serotonin reuptake inhibitors (SSRIs) with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., sumatriptan). Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome and can be life-threatening. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SSRI or the addition of other serotonergic medications to an existing SSRI regimen. Sibutramine: (Major) Sibutramine is a serotonin reuptake inhibitor. Concomitant use of two serotonin-augmenting drugs has been associated with serotonin syndrome, so concurrent use of the serotonin-receptor agonists with sibutramine is not recommended. St. John's Wort, Hypericum perforatum: (Major) Although unlikely to occur during monotherapy with 5-HT1 agonists such as sumatriptan, serotonin syndrome may occur from combining medications that potentiate serotonin activity. Serotonin syndrome, while uncommon, can be serious and consists of symptoms such as mental status changes, diaphoresis, tremor, myoclonus, hyperreflexia, and fever. St. John's wort, Hypericum perforatum can potentiate the effects of serotonin through inhibiting serotonin reuptake. Tapentadol: (Major) Caution is advised when tapentadol is coadministered with serotonin-receptor agonists, as this combination may increase the potential for serotonin syndrome development. If concomitant treatment is clinically warranted, careful observation of the patient is advised, especially during initiation of the second therapy and after dosage adjustments (increases) of either agent. Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and serotonin-receptor agonists such as sumatriptan. Tedizolid is an antibiotic that is also a weak reversible, non-selective inhibitor of MAO. The monoamine oxidase (MAO) type A enzyme metabolizes serotonin. Non-selective traditional MAO inhibitors increase the plasma concentrations of these drugs and some of their active metabolites, thus increasing levels of serotonin. Serious CNS reactions, such as serotonin syndrome, have been reported during the concurrent use of linezolid, which is structurally similar to tedizolid, and psychiatric medications that enhance central serotonergic activity; therefore, caution is warranted with concomitant use of other agents with serotonergic activity. This interaction could lead to 'serotonin syndrome' (presenting as agitation, restlessness, aggressive behavior, insomnia, poor concentration, headache, paresthesia, incoordination, worsening of obsessive thoughts or compulsive behavior, nausea, abdominal cramps, diarrhea, palpitations, or chills). The manufacturers of serotonin agonists contraindicate the administration of their drugs to patients receiving non-selective MAO inhibitors or within 2 weeks of discontinuation of a MAO inhibitor. Tramadol: (Moderate) Caution is advised when tramadol is coadministered with serotonin-receptor agonists because of the potential for serotonin syndrome. If concomitant treatment of tramadol and a serotonin-receptor agonist is clinically warranted, careful observation of the patient is advised, especially during the initial time both drugs are used together and during a dose increase of either tramadol or the serotonin-receptor agonist. Tranylcypromine: (Severe) Concurrent administration of MAO-A inhibitors or use of sumatriptan within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated. Sumatriptan appears to metabolized by monoamine oxidase (MAO), predominantly MAO-type A; therefore, plasma concentrations of sumatriptan may be increased by concurrent use of selective MAO-A inhibitors (e.g., meclobemide) or non-selective MAO-A and MAO-B inhibitors (e.g., phenelzine, tranylcypromine, isocarboxazid). Because oral sumatriptan usually undergoes first-pass metabolism, the increase of AUC after coadministration of an MAO-A inhibitor is greater than the interaction with subcutaneous sumatriptan combined with an MAO-A inhibitor. The effects of an MAOI on the AUC after intranasal sumatriptan use would be expected to be greater than the effect after sumatriptan SC but smaller than the effect after sumatriptan PO. In a study of healthy female volunteers (n=14), pretreatment with an MAO-A inhibitor (moclobemide) decreased the clearance of subcutaneous sumatriptan resulting in a 2-fold increase in sumatriptan AUC and a 40% increase in elimination half-life. The interaction was not evident with an MAO-B inhibitor (e.g., selegiline). In a similar study of oral sumatriptan, pretreatment with an MAO-A inhibitor followed by 25-mg PO of sumatriptan resulted in an approximately 7-fold increase in sumatriptan AUC. Trazodone: (Major) Based on the mechanism of action of trazodone and the potential for serotonin syndrome, caution is advised when trazodone is coadministered with other drugs that may affect these neurotransmitter systems, including the serotonin-receptor agonists ("triptans"). The co-use of serotonergic antidepressants with serotonin-agonists has sometimes resulted in serotonin syndrome. Careful observation of the patient is advised, particularly during treatment initiation and dose increases. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Discontinue the serotonergic agents immediately if serotonin syndrome reactions occur and initiate supportive symptomatic treatment. Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Trimipramine: (Moderate) Tricyclic antidepressants (TCAs) should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Tricyclic antidepressants inhibit norepinephrine and serotonin uptake, but rarely cause serotonin syndrome when used alone. However, the risk may be increased when combined with other serotonergic agents, especially at times of antidepressant dose increases. Venlafaxine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering a selective serotonin norepinephrine reuptake inhibitor (SNRI) like venlafaxine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) because of the potential risk and severity of serotonin syndrome. Serotonin syndrome has been reported during concurrent use of drugs from these drug classes. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the SNRI or the addition of other serotonergic medications to an existing SNRI regimen. Vilazodone: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vilazodone with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) with serotonin-receptor agonists. Of the 27 cases reviewed by the FDA, 2 were considered life-threatening and 13 required hospitalization. Some patients had used the combination previously without incident. Eight of 27 cases involved a recent dose increase or addition of another serotonergic drug to the regimen, with a median onset of 1 day (range: 10 minutes to 6 days). It is thought that the interaction between SNRIs or SSRIs and serotonin-receptor agonists is the result of increased serotonergic activity by each of the drug classes. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. At least 6 patients taking an SSRI antidepressant are known to have received sumatriptan for migraine where no apparent adverse effects were seen. In another case report, the addition of fluoxetine lead to loss of migraine control with sumatriptan. Patients receiving vilazodone and a serotonin-receptor agonist should be monitored for the emergence of serotonin syndrome, particularly during treatment initiation and during dosage increases. Vilazodone and the serotonin-receptor agonist should be discontinued if serotonin syndrome occurs and supportive symptomatic treatment should be initiated. Vortioxetine: (Major) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering vortioxetine with other drugs that have serotonergic properties such as serotonin-receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). Serotonin syndrome has been reported during concurrent use of serotonergic antidepressants with the serotonin-receptor agonists. Some patients had used the combination previously without incident when serotonin syndrome occurred. Some cases have involved hospitalization. Serotonin syndrome consists of symptoms such as mental status changes (e.g., agitation, confusion, hallucinations), diaphoresis, hyperreflexia, hypertension, diarrhea, fever, tremor, and, in some instances, respiratory failure. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome. Careful monitoring for serotonin syndrome is recommended if combination therapy with is required. Risk factors can include a recent dose increase of the sertonergic antidepressant or the addition of other serotonergic medications to an existing antidepressant regimen.

PREGNANCY AND LACTATION

Pregnancy

A consistent pattern of birth defects among pregnant women exposed to sumatriptan has not been observed. The sumatriptan prospective pregnancy registry collected pregnancy outcomes of 528 infants and fetuses with earliest sumatriptan exposure during the first trimester, 78 during the second trimester, and 16 during the third trimester. The incidence of major birth defects during first trimester exposure was 4.2% (20/478 [95% CI 2.6% to 6.5%]) and during any trimester exposure was 4.2% (24/576 [95% CI 2.7% to 6.2%]). Birth defects reported for more than 2 infants after first trimester exposure included ventricular septal defects (n = 4) and pyloric stenosis (n = 3). Fetal deaths, spontaneous abortions, and elective abortions without reported defects were excluded from analysis. An analysis of data from the Swedish Medical Birth Register reported a relative risk of malformations of 0.99 (107/2,257 [95% CI 0.91 to 1.21]) among live births with first trimester exposure to sumatriptan. A study of the Norwegian birth registry and prescription data reported congenital malformations in 15 infants of 415 women who redeemed prescriptions for sumatriptan during the first trimester of pregnancy, and in 20 infants of 364 women who redeemed prescriptions for sumatriptan before, but not during, pregnancy. Compared to a general population group, the odds ratio for congenital malformation was 1.16 (95% CI 0.69 to 1.94) among women who redeemed prescriptions for sumatriptan during the first trimester and 1.83 (95% CI 1.17 to 2.88) for those who redeemed prescriptions for sumatriptan before pregnancy. During animal reproductive studies, intravenous administration of sumatriptan to rabbits during organogenesis resulted in an increased incidence of embryolethality with a no-effect dose of 0.75 mg/kg/day, which is approximately one tenth of the maximum single oral dose of 100 mg based on body surface area. In rats and rabbits, oral treatment with sumatriptan was associated with fetal abnormalities and pup mortality at doses higher than the maximum single recommended human oral dose based on body surface area.

Sumatriptan is excreted into the breast milk of humans. Previous American Academy of Pediatrics recommendations considered sumatriptan to be compatible with breast-feeding. Infant exposure to sumatriptan can be minimized by avoiding breast-feeding for 12 hours after treatment. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for sumatriptan and any potential adverse effects on the breast-fed infant from sumatriptan or the underlying maternal condition. In 1 trial, 5 women who had been lactating for an average of 22 weeks received a single 6 mg subcutaneous dose of sumatriptan. Drug concentrations were measured in milk and plasma over an 8 hour period after drug administration. The mean milk:plasma ratio of sumatriptan was 4.9 (95% CI 4.1 to 5.7), indicating a significant transfer of sumatriptan into the milk compartment. However, only 0.24% (14 mcg; CI 6.1 to 22.7 mcg) of the 6 mg sumatriptan dose was recovered in the milk, which corresponds to a weight-adjusted mean exposure of 3.5% (95% CI 0.3% to 6.7%) of the maternal dose. Assuming oral bioavailability of sumatriptan in infants is similar to adults (mean 14%), the weight-adjusted infant dose is roughly 0.49%. Allowance for reduced clearance in the infant predicts an infant exposure varying from 4.9% in the very premature neonate to 0.7% in a 30 week old infant (mean 3.5%). The authors of this study concluded that expressing breast milk and discarding it up to 8 hours after a dose would help to avoid any potential infant exposure to sumatriptan.

MECHANISM OF ACTION

Mechanism of Action: The introduction of sumatriptan changed the treatment strategies for migraine. The search for a new approach to therapy was preceded by the observation that changes in serotonin levels parallel migraine attacks. Platelet serotonin levels have been shown to increase before a migraine attack and decrease during an attack. In addition, artificially depleted serotonin levels produce typical headaches. The pathophysiology of migraine is not completely understood, however, and therefore the action of the serotonin-agonists (i.e., 'triptans' ) in treating migraine is not completely certain. Multiple pharmacological actions have been derived that appear important for antimigraine effects.. 'Triptans' stimulate presynaptic 5-HT1D receptors, an action that inhibits both dural vasodilation and inflammation. They directly inhibit trigeminal nuclei cell nociceptive neurotransmission via 5-HT1B/D receptor agonism within the trigeminocervical complex of the brainstem and upper spinal cord. Additionally, vascular 5-HT1B receptor agonism results in vasoconstriction of painfully dilated intracranial extracerebral vessels.. Sumatriptan has no pharmacologic activity at dopaminergic, muscarinic, or sympathetic receptors and does not possess intrinsic analgesic properties. Animal studies have shown that sumatriptan decreases carotid arterial blood flow but only slightly affects blood pressure; it has little effect on diastolic blood pressure or total peripheral resistance. In dogs, sumatriptan selectively reduces carotid arterial blood flow without affecting arterial blood pressure or total peripheral resistance. Sumatriptan exhibits activity at coronary 5-HT1B receptors, but the drug is 10 times more potent in the middle meningeal arteries than the human coronary arteries . In general, therapeutic concentrations of sumatriptan and other 'triptans' in patients with normal coronary circulation are unlikely to produce cardiac ischemia; second generation agents have been less likely than sumatriptan in laboratory studies to induce coronary vasocontriction. However, in therapeutic use, elevated blood pressure, chest pain and other cardiac events have been rarely reported with all 'triptans'.

PHARMACOKINETICS

Sumatriptan is administered orally, subcutaneously, intranasally, or transdermally. Sumatriptan is widely distributed throughout the body. Protein binding ranges from 14 to 21%. Approximately 80% of a dose is hepatically metabolized. Metabolism produces an inactive metabolite and its glucuronide conjugate. Renal clearance is believed to be by tubular secretion as well as glomerular filtration. The mean terminal half-life is 1.9 hours. A large percentage of patients who received initial relief with sumatriptan will experience the return of their migraine. In one study of 453 patients, 75% experienced headache recurrence in at least some episodes treated with sumatriptan.

Oral Route

Oral absorption of sumatriptan, though influenced by variable gastric emptying and small-bowel transit, is rapid. The onset of relief of migraine-associated symptoms is approximately 60 minutes. Peak concentration is achieved within 2 hours; in clinical study, peak relief was achieved in about 2 hours for 54% of patients and 4 hours for an additional 17%. Bioavailability is about 15% following oral administration. Poor bioavailability after oral administration results from incomplete absorption and first-pass hepatic metabolism. Following oral administration, about 60% is excreted renally primarily as the IAA metabolite with approximately 3% as unchanged drug; the remaining 40% is excreted in the feces.

Subcutaneous Route

Subcutaneous absorption of sumatriptan has been shown to give more consistent blood plasma peak concentrations than are achieved from administration by other routes. Peak concentration is achieved within 5 to 20 minutes via the subcutaneous route. Onset of pain relief after subcutaneous injection can occur within 10 minutes, and as many as 80% of patients experience relief within 60 minutes. The onset of relief of migraine-associated symptoms is approximately 20 minutes. The time to peak relief for subcutaneous injection is 1 hour in 68% of patients and 2 hours in an additional 13% of patients. Bioavailability after subcutaneous injection is about 97%; distribution half-life is about 13 minutes. After subcutaneous administration, about 22% of a sumatriptan dose is excreted unchanged in the urine and 38% as the indole acetic acid (IAA) metabolite, with a small amount of excretion occurring in the feces. A single 3 mg subcutaneous dose of Zembrace SymTouch is bioequivalent to Imitrex subcutaneous injection.

Other Route(s)

Intranasal RouteNasal SprayIntranasal absorption is rapid with peak concentration of sumatriptan achieved within 1 to 1.75 hours. Only 3% of the dose is renally eliminated as unchanged drug, with 42% eliminated as the major metabolite.

Nasal PowderPeak plasma concentration occurred on average at 45 minutes following administration. The relative bioavailability compared to subcutaneous injection is approximately 19%. The half-life is approximately 3 hours when administered as a nasal powder.

Transdermal RouteAfter application of the sumatriptan transdermal system (TDS) to the upper arm, peak plasma concentrations are reached in 1.1 hours. The mean Cmax and mean AUC0-inf were approximately 37% and 45%, respectively, of the values measured after oral administration of 100 mg sumatriptan tablets. The relative bioavailability of sumatriptan following application of the TDS to the upper thigh is comparable to that after application to the upper arm, thus the sites are considered interchangeable. After a single dose in 9 subjects, 11% of the sumatriptan dose was excreted in the urine as unchanged sumatriptan and 69% as the indole acetic acid metabolite. The mean sumatriptan half-life was 3.1 hours after a single TDS dose.

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